CN112250567B - Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol - Google Patents
Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol Download PDFInfo
- Publication number
- CN112250567B CN112250567B CN202011244915.9A CN202011244915A CN112250567B CN 112250567 B CN112250567 B CN 112250567B CN 202011244915 A CN202011244915 A CN 202011244915A CN 112250567 B CN112250567 B CN 112250567B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- bis
- chiral
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
- C07C29/177—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds with simultaneous reduction of a carboxy group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing AMG837 and chiral gamma-methyl phenylpentanol, which takes racemic propargyl carbonate and a methane tricarboxylate compound as initial raw materials, takes bis- (1, 5-cyclooctadiene) nickel metal as a catalyst, a chiral phosphine reagent as a ligand and Lewis acid as an additive, and respectively carries out two synthetic routes of asymmetric propargylation reaction, hydrolysis reaction, decarboxylation reaction and asymmetric propargylation reaction, hydrolysis reaction, decarboxylation reaction, hydrogenation reaction and reduction reaction under the assistance of alkali, thereby accurately and quickly synthesizing the AMG837 and the chiral gamma-methyl phenylpentanol compound with high yield, high enantioselectivity and gram-scale. The invention not only successfully develops the synthetic method of the AMG837 and the chiral gamma-methyl benzene amyl alcohol, but also easily prepares the AMG837 and the chiral gamma-methyl benzene amyl alcohol compound with high yield and high optical purity, and simultaneously, the method also has the biomedical practicability and the industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of asymmetric organic synthesis, and particularly relates to a synthetic method of AMG837 and chiral gamma-methyl phenylpentanol.
Background
In the modern society, with the rapid development of economy and the improvement of living standard of people, human health is facing the threat of various diseases. Among them, the global prevalence of type 2 diabetes (T2DM) is now approaching 3 billion diabetic patients and is increasing at a rapid rate, placing tremendous pressure on the healthcare system worldwide. Type 2 diabetes mellitus is manifested by a variety of metabolic defects, the most prominent of which are increased resistance of body tissues to the action of insulin and a marked decrease in the insulin secretory response of the pancreas to glucose load. In response to the latter of these two deficiencies, sulfonylurea insulin secretagogues inhibit ATP-sensitive potassium channels present in islet β cells and cause sustained increases in insulin release. However, this mechanism of increasing insulin secretion is insensitive to plasma glucose levels and may lead to over-release, resulting in hypoglycemia with symptoms of sweating, nervousness, dizziness and obnubilation. The ability of free fatty acids to increase insulin secretion has been extensively studied in vitro and in vivo. Through identification, GPR40 is used as a free fatty acid receptor expressed by pancreatic islets, can promote calcium ion inflow of pancreatic islet beta cells, secretes insulin, and plays a role in inhibiting blood sugar rise. Notably, the increase in insulin secretion caused by GPR40 is only present when the glucose level is elevated. And the AMG837 serving as a GPR40 agonist can achieve the purpose of controlling blood sugar by activating a GPR40 receptor, so that the development of a synthetic method of the AMG837 has a very wide medicinal value.
Also because of its interesting biological properties, the study of asymmetric synthesis of AMG837 has attracted widespread commercial and scientific interest. So far, several routes have been reported for the synthetic method of AMG837 (CN110590767, org.lett.2011,13,952, angelw.chem.int.ed.2013, 52,7532, bioorg.med.chem.lett.2012, 22,1267), but these methods have problems of long synthetic route, low yield, poor enantioselectivity, need to perform chiral resolution or difficult realization of amplified mass preparation, and therefore, it is very necessary to explore a novel synthetic route for preparing AMG837 rapidly and specifically in a stereoselective manner starting from a simple and easily available racemic molecular skeleton.
Gamma-methyl amyl alcohol is also called as rose alcohol and is a common series of essence and spice with rose fragrance. Also, due to its unusual fragrance and durability, it is widely used in high-grade daily necessities and skin care products. It is well known that there is a significant difference in odor threshold between compounds of opposite configuration, and therefore the synthesis of chiral γ -methyl phenylpentanol has a wide commercial prospect in perfumery applications. However, due to the lack of efficient enantioselective synthesis of chiral γ -methylbenzyl-pentanol, the market is now mainly using racemic γ -methylbenzyl-pentanol as a perfume additive. Although there are reports on the synthesis of chiral γ -methyl phenylpentanol at present (Chirality2011,23,761, Acs cat.2016, 6,8342, org.lett.2019,21, 3247), it is necessary to develop a novel synthetic route for rapidly preparing chiral γ -methyl phenylpentanol in a stereoselective manner due to the disadvantages of longer synthetic route, lower yield or difficulty in industrial preparation.
Disclosure of Invention
The invention aims to provide a method for synthesizing AMG837 and chiral gamma-methyl amyl benzene, thereby solving the problems in the prior art.
The synthetic method of AMG837 of the invention comprises the following steps:
step 1: under the argon atmosphere, mixing a bis- (1, 5-cyclooctadiene) nickel metal catalyst and a chiral phosphine ligand in an organic solvent, pre-stirring for 15 minutes, then under the protection of argon, adding a racemic propargyl carbonate compound A, a methane tricarboxylate compound B and alkali into a mixed system, reacting for 12-96 hours at the temperature of room temperature to 50 ℃, and determining a reaction end point by using a thin-layer chromatography dot plate; diluting the reaction system with ethyl acetate, adding water for extraction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography with petroleum ether/ethyl acetate (4:1, v/v) as eluent to obtain asymmetric propargylated product C;
step 2: stirring the asymmetric propargylated product C in an organic solvent under an air atmosphere, and adding an aqueous sodium hydroxide solution (3N) to the reaction system, followed by stirring the mixture at room temperature to 80 ℃ and monitoring by TLC; when no starting raw material exists in the reaction system, removing volatile matters in vacuum, adding acetic acid into the reaction system, and heating to react for 6-12 hours under the reflux condition; after the reaction is finished, acetic acid is concentrated in vacuum, the reaction system is diluted by ethyl acetate and extracted by adding water, then the water phase is extracted by ethyl acetate for 3 times, the organic phase is combined, dried by anhydrous sodium sulfate and concentrated under reduced pressure, and then petroleum ether/ethyl acetate (1:1, v/v) is used as an eluent to obtain AMG837 or an enantiomer thereof through column chromatography separation.
In the step 1, the molar ratio of the bis- (1, 5-cyclooctadiene) nickel metal catalyst, the chiral phosphine ligand and the methane tricarboxylate compound B is 0.1:0.12: 1; the molar equivalent ratio of the methane tricarboxylate compound B to the racemic propargyl carbonate compound A is 1: 1-3; the molar ratio of the methane tricarboxylate compound B to the alkali is 1: 1-3.
The reaction route of the preparation process of the AMG837 is as follows:
in the formula: represents a chiral carbon atom; substituent R1Selected from methyl, ethyl, tert-butyl; substituent R2Selected from methyl, ethyl, benzyl.
The method for synthesizing the chiral gamma-methyl amyl alcohol comprises the following steps:
step 1: under the argon atmosphere, mixing a bis- (1, 5-cyclooctadiene) nickel metal catalyst and a chiral phosphine ligand in an organic solvent, pre-stirring for 15 minutes, then under the protection of argon, adding a racemic propargyl carbonate compound E, a methane tricarboxylate compound F, an alkali and a Lewis acid into a mixed system, reacting for 12-96 hours at the temperature of room temperature to 50 ℃, and determining a reaction end point by using a thin-layer chromatography dot plate; diluting the reaction system with ethyl acetate, adding water for extraction, extracting the water phase with ethyl acetate for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography with petroleum ether/ethyl acetate (19:1, v/v) as eluent to obtain asymmetric propargylated product G;
step 2: stirring the asymmetric propargylated product G in an organic solvent under an air atmosphere, adding an aqueous sodium hydroxide solution (3N) to the reaction system, and subsequently stirring the mixture at room temperature to 80 ℃ and monitoring by TLC; when no starting raw material exists in the reaction system, removing volatile matters in vacuum, adding acetic acid into the reaction system, and heating to react for 6-12 hours under the reflux condition; after the reaction is finished, concentrating acetic acid in vacuum, diluting the reaction system with ethyl acetate, adding water for extraction, extracting a water phase with ethyl acetate for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by using petroleum ether/ethyl acetate (1:1, v/v) as an eluent through column chromatography to obtain a compound H;
and step 3: dissolving a compound H in an organic solvent in an air environment, slowly adding palladium/carbon at room temperature, and reacting at room temperature to 70 ℃ for 6-12 hours in a hydrogen atmosphere with one atmosphere of pressure; after the reaction is finished, adding ethyl acetate into the reaction system for dilution, filtering through diatomite, concentrating the filtrate under reduced pressure until the filtrate is dry, and using the residue in the next step without purification; and slowly adding the crude product obtained in the previous step into a mixture of lithium aluminum hydride and an organic solvent at 0 ℃, heating the mixture to room temperature, stirring for 6-12 hours, quenching the reaction with sodium sulfate decahydrate at 0 ℃, filtering through diatomite, concentrating the filtrate under reduced pressure to dryness, and separating the residue by column chromatography by using petroleum ether/ethyl acetate (4:1, v/v) as an eluent to obtain chiral gamma-methyl benzene pentanol I.
In the step 1, the molar ratio of the bis- (1, 5-cyclooctadiene) nickel metal catalyst, the chiral phosphine ligand and the methane tricarboxylate compound F is 0.1:0.12: 1; the molar equivalent ratio of the methane tricarboxylate compound F to the racemic propargyl carbonate compound E is 1: 1-3; the molar ratio of the methane tricarboxylate compound F to the alkali is 1: 1-3; the amount of the Lewis acid added was 0.2 equivalent to that of the methyl trimethyl ester compound F.
In the step 3, the addition amount of palladium/carbon is 0.1-0.5 time equivalent of the compound H; the addition amount of the lithium aluminum hydride is 1.0-2.0 times of the equivalent of the compound H;
the preparation process of the chiral gamma-methyl amyl alcohol can be represented by the following reaction formula:
in the formula: represents a chiral carbon atom; substituent R3Selected from methyl, ethyl, tert-butyl; substituent R4Selected from methyl, ethyl, benzyl.
In the preparation process, the alkali is cesium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium hydride.
In the preparation process, the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, toluene, methanol, ethanol, ethyl acetate, 1, 2-dichloroethane, N-dimethylformamide or dimethyl sulfoxide.
In the preparation process, the chiral phosphine ligand is (R or S) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, (R or S) -5,5' -bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl, (R or S) -2,2' -bis [ di (4-methylphenyl phosphine) ] -1,1' -binaphthyl or (R or S) -5,5' -bis (diphenylphosphoryl) -tetrafluoro-di-1, 3-benzodioxole.
In the preparation process, the Lewis acid is copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate or scandium trifluoromethanesulfonate.
The invention provides a method for synthesizing AMG837 and chiral gamma-methyl benzene amyl alcohol through key steps of asymmetric propargylation reaction. The method takes racemic propargyl carbonate and a methane tricarboxylate compound as initial raw materials, takes bis- (1, 5-cyclooctadiene) nickel metal as a catalyst, a chiral phosphine reagent as a ligand and Lewis acid as an additive, and carries out two synthetic routes of asymmetric propargyl reaction, hydrolysis reaction, decarboxylation reaction and asymmetric propargyl reaction, hydrolysis reaction, decarboxylation reaction, hydrogenation reaction and reduction reaction under the assistance of alkali, so that the AMG837 and the chiral gamma-methyl phenylpentanol compound are accurately and quickly synthesized with high yield, high enantioselectivity and gram-scale. The invention not only successfully develops the synthetic method of the AMG837 and the chiral gamma-methyl benzene amyl alcohol, but also easily prepares the AMG837 and the chiral gamma-methyl benzene amyl alcohol compound with high yield and high optical purity, and simultaneously, the method also has the biomedical practicability and the industrial application prospect.
Drawings
FIG. 1 is a preparation scheme of example 1.
Figure 2 is a preparation scheme for example 2.
Detailed Description
Example 1: preparation of (-) -AMG837
1. 3-bromobenzyl alcohol (1.0 equivalent) was dissolved in anhydrous THF under nitrogen atmosphere and stirred under ice bath, followed by addition of triphenylphosphine (1.1 equivalent) in portions to the mixture and dropwise addition of diisopropyl azodicarboxylate (1.1 equivalent) to the reaction system. The reaction mixture was then stirred at 0 ℃ for 1 hour and then at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, the organic phase was washed successively with a saturated aqueous sodium hydrogencarbonate solution and a sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily residue. The desired ether derivative S1 was then isolated by column chromatography using petroleum ether/ethyl acetate (9:1) as eluent.
White solid (65%)1H NMR(400MHz,CDCl3)δ9.89(s,1H),7.80-7.98(m,2H),7.60(s,1H), 7.40–7.54(m,1H),7.34–3.39(m,1H),7.23–7.33(m,1H),7.03–7.13(m,2H),5.12(s,2H).13C NMR(100MHz,CDCl3)δ190.76,163.34,138.24,132.04,131.41,130.36,130.30,125.85,122.82, 115.11,62.29.
2. A solvent mixture of methanol (0.5M), toluene (0.125M) and aqueous potassium carbonate (2.0 equiv.) was sonicated at room temperature for 30 minutes, then flushed with nitrogen for 30 minutes at room temperature. Subsequently, bromobenzene derivative S1(1.0 equivalent), p-trifluoromethylphenylboronic acid (1.25 equivalent) and tetratriphenylphosphine palladium (0.024 equivalent) were added successively to the reaction system under nitrogen blanket, and the reaction mixture was stirred under reflux overnight. After completion of the reaction, the reaction system was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was diluted with ethyl acetate, the organic phase was washed successively with water, saturated aqueous sodium bicarbonate solution and brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. Then the desired biaryl derivative S2 was isolated by column chromatography using petroleum ether/ethyl acetate (9:1) as eluent.
White solid (70% yield)1H NMR(400MHz,CDCl3)δ9.92(s,1H),7.88(d,J＝8.8Hz,2H), 7.66–7.82(m,5H),7.48–7.70(m,3H),7.12(d,J＝8.8Hz,2H),5.24(s,2H).13C NMR(400MHz, CDCl3)δ190.80,163.57,144.28,140.35,136.78,132.06,130.23,129.42,127.48,127.28,127.22, 126.36,125.80,115.11,70.07.
3. To a dry 100mL round bottom flask was added the biaryl derivative S2(10mmol), the flask was placed under nitrogen and cooled to-78 ℃. Subsequently, a solution of 1-propynyl magnesium bromide (22mL, 0.5M in THF, 1.1 eq.) was added slowly to the reaction and the mixture was stirred at-78 deg.C for 1 hour, then allowed to warm to room temperature and stirred for an additional 2 hours. After the reaction was complete, saturated aqueous ammonium chloride was slowly added to the mixture in an ice bath, the aqueous phase was extracted 3 times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give propargyl compound S3 which was used directly in the next reaction without further purification.
4. Di-tert-butyl dicarbonate (1.0 equivalent), triethylamine (1.5 equivalents) and 4-dimethylaminopyridine (1.0 equivalent) were dissolved in a tetrahydrofuran solution (0.3M) under an air atmosphere, then the propargyl compound S3(1.0 equivalent) was added dropwise, the progress of the reaction was monitored by TLC, the reaction was quenched with a saturated aqueous ammonium chloride solution after the end of the reaction and extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. Then petroleum ether/ethyl acetate (9:1) is used as eluent to obtain the required propargyl carbonate raw material 1 through column chromatography separation.
Yellow oil (75% yield)1H NMR(500MHz,CDCl3)δ7.73–7.68(m,4H),7.66(s,1H),7.58 –7.54(m,1H),7.51–7.41(m,4H),6.98–6.94(m,2H),5.18(q,J＝2.2,1H),5.13(s,2H),1.86(d, J＝2.1Hz,3H),1.31(s,9H).19F NMR(470MHz,CDCl3)δ-62.40(s).13C NMR(125MHz, CDCl3)δ158.27,144.58,140.29,138.10,134.70,129.61(q,J＝32.1Hz),129.40,128.27,127.64, 127.38,127.03,126.49,125.88(q,J＝3.8Hz),124.41(q,J＝270.0Hz),114.76,81.91,80.68, 75.41,70.01,64.03,28.61,4.02.ATR-FTIR(cm-1):2971,2921,2852,2221,1754,1510,1469, 1367,1326,1240,1126,1072,842,790.ESI-MS:calculated[C29H27F3O4+Na]+:519.1754,found: 519.1760.
5. To a dry 100mL Schlenk reaction tube under a glove box nitrogen atmosphere were added bis- (1, 5-cyclooctadiene) nickel (132mg,0.48mmol,10 mol%) and (R) -5,5 '-bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl (354mg,0.58 mmol,12 mol%), and 60mL of toluene was added and stirred for 15 minutes; then under nitrogen protection, 7.2mmol 1(3.58 g, 1.5 equivalents), 4.8mmol 2(1115mg, 1.0 equivalents) and cesium carbonate (3.1g, 9.6mmol, 2.0 equivalents) were added to the reaction tube in sequence and the reaction was stirred at room temperature for about 96 hours until substrate 2 was completely consumed (monitored by TLC); the reaction was then diluted with ethyl acetate and extracted with water, the aqueous phase was then extracted 3 times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography using petroleum ether/ethyl acetate (4:1) as eluent to give asymmetric propargylated product 3(2.65g, 90% yield, 94% ee).
Colorless oil (2.65g, 90% yield)1H NMR(400MHz,CDCl3)δ7.73–7.67(m,4H),7.66–7.62 (m,1H),7.57–7.42(m,5H),6.93–6.86(m,2H),5.11(s,2H),4.71(q,J＝2.3Hz,1H),4.24– 4.09(m,6H),1.82(d,J＝2.5Hz,3H),1.20(t,J＝7.1Hz,9H).19F NMR(375MHz,CDCl3)δ -62.41(s).13C NMR(100MHz,CDCl3)δ165.45,158.34,144.55,140.27,138.05,131.68,129.62 (q,J＝32.0Hz),129.38,129.30,127.62,127.34,127.00,126.44,125.86(q,J＝4.0Hz),124.41(q, J＝271.0Hz),114.13,80.35,77.35,70.34,69.88,62.08,40.55,13.96,3.87.ATR-FTIR(cm-1): 2983,2923,2243,1747,1058,1465,1367,1243,1126,1072,844,790,700.ESI-MS:calculated [C34H33F3O7+H]+:611.2251,found:611.2234.[α]20 D＝-17.3(c＝1.00,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:94％ee(IC,hexane/i-PrOH＝95/5, detector:254nm,flow rate:1.0mL/min),t1(minor)＝19.8min,t2(major)＝23.8min.
6. Asymmetric propargylated product 3(2550mg,4.18mmol) was stirred in 40mL of methanol under air, and 10mL of aqueous sodium hydroxide (3N) was added to the reaction, followed by stirring of the mixture at reflux temperature and monitoring by TLC. When no starting material was present in the reaction system, the volatiles were removed in vacuo and 40mL of acetic acid was added to the reaction system and heated to reflux for 12 hours. After the reaction was complete, (-) -AMG837 (1.62g, 88% yield, 94% ee) was obtained by column chromatography using petroleum ether/ethyl acetate (1:1) as eluent.
Yellow oil (1.62g, 88% yield)1H NMR(400MHz,CDCl3)δ7.71–7.63(m,5H),7.54(d,J＝ 6.9Hz,1H),7.50–7.42(m,2H),7.31(d,J＝8.3Hz,2H),6.95(d,J＝8.3Hz,2H),5.10(s,2H), 4.10–4.01(m,1H),2.87–2.64(m,2H),1.82(s,3H).19F NMR(375MHz,CDCl3)δ-62.34 (s).13C NMR(100MHz,CDCl3)δ177.25,157.92,144.52,140.26,137.99,133.57,129.60(q,J＝ 32.0Hz),129.40,128.58,127.60,127.38,127.04,126.46,125.86(q,J＝3.0Hz),124.41(q,J＝ 271.0Hz),115.10,79.50,79.26,70.01,43.42,33.27,3.77.ATR-FTIR(cm-1):2921,2237,1712, 1508,1328,1243,1124,842,790,700.ESI-MS:calculated[C26H21F3O3+H]+:439.1516found: 439.1524.[α]20 D＝-10.2(c＝1.11,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:94％ee(AD-H,hexane/i-PrOH＝80/20,detector:254nm,flow rate:1.0 mL/min),t1(major)＝12.5min,t2(minor)＝20.6min.
Example 2: preparation of (+) -gamma-methyl benzene pentanol
1. To a dry 100mL Schlenk reaction tube under a glove box nitrogen atmosphere were added bis- (1, 5-cyclooctadiene) nickel (137.5mg,0.5mmol,10 mol%) and (R) -5,5 '-bis (diphenylphosphoryl) -4,4' -bis-1, 3-biphenyl (366.4mg,0.6 mmol,12 mol%), and 60mL dichloromethane was added and stirred for 15 minutes; then 7.5mmol 5 (1.85g, 1.5 equivalents) (synthesis reference: org.lett.2015,17,5871.), 5.0mmol 2(1160mg, 1.0 equivalents), ytterbium triflate (620.2mg,1.0mmol,20 mol%) and cesium carbonate (3.3g,10.0mmol,2.0 equivalents) were added to the reaction tube sequentially under nitrogen protection and the reaction was stirred at room temperature for about 96 hours until substrate 2 was completely consumed (monitored by TLC); the reaction was then diluted with ethyl acetate and extracted with water, the aqueous phase was then extracted 3 times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography using petroleum ether/ethyl acetate (19:1) as eluent to give asymmetric propargylated product 6(1.54g, 85% yield, 93% ee).
Colorless oil (1.54g, 85% yield)1H NMR(500MHz,CDCl3)δ7.39–7.33(m,2H),7.29–7.24 (m,3H),4.29(q,J＝7.1Hz,6H),3.68(q,J＝7.0Hz,1H),1.50(d,J＝7.0Hz,3H),1.29(t,J＝7.1 Hz,9H).13C NMR(125MHz,CDCl3)δ165.85,131.67,128.22,127.93,123.53,89.84,82.41, 69.08,62.26,30.88,17.68,14.09.ATR-FTIR(cm-1):2981,2923,2854,2242,1743,1598,1463, 1367,1261,1095,862,757,692.ESI-MS:calculated[C20H24O6+H]+:361.1646,found:361.1650. [α]20 D＝-31.2(c＝1.11,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:93％ee(OD-H,hexane/i-PrOH＝99/1,detector:254nm,flow rate:1.0 mL/min),t1(minor)＝11.1min,t2(major)＝12.8min.
2. Asymmetric propargylated product 6(1449mg,4.0mmol) was stirred in 40mL of methanol under air, and 10mL of aqueous sodium hydroxide (3N) was added to the reaction, followed by stirring of the mixture at reflux temperature and monitoring by TLC. When no starting material was present in the reaction system, the volatiles were removed in vacuo and 40mL of acetic acid was added to the reaction system and heated to reflux for 12 hours. After the reaction was completed, acetic acid was concentrated in vacuo, the reaction was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then compound 7(0.69g, 91% yield) was isolated by column chromatography using petroleum ether/ethyl acetate (1:1) as eluent.
Colorless oil (0.69g, 91% yield)1H NMR(400MHz,CDCl3)δ7.42–7.35(m,2H),7.28–7.26 (m,3H),3.23–3.11(m,1H),2.76–2.65(m,1H),2.63–2.46(m,1H),1.34(d,J＝6.9Hz,3H).13C NMR(125MHz,CDCl3)δ177.61 131.77,128.32,127.96,123.53,92.28,81.42,41.50,23.32, 20.87.ATR-FTIR(cm-1):2926,2210,1780,1710,1520,1470,846,750.ESI-MS:calculated [C12H12O2+H]+:189.0910,found:189.0913.
3. Compound 7(685.7mg,3.64mmol) was dissolved in 30mL of methanol solvent under an air atmosphere, 10% palladium on carbon (69mg) was slowly added at room temperature, and reacted under a hydrogen atmosphere of one atmosphere at room temperature for 12 hours; after the reaction was completed, ethyl acetate was added to the reaction system to dilute, and filtered through celite, the filtrate was concentrated to dryness under reduced pressure, and the residue was used in the next step without purification. The crude product from the previous step was then added slowly to a mixture of lithium aluminium hydride (690.7mg,5.0mmol) in 20mL of tetrahydrofuran solvent at 0 ℃, after the mixture was allowed to warm to room temperature and stirred for 12 hours, the reaction was quenched with sodium sulphate decahydrate at 0 ℃ and filtered through celite, the filtrate was concentrated to dryness under reduced pressure, and the residue was separated by column chromatography using petroleum ether/ethyl acetate (4:1) as eluent to give (+) -gamma-methylbenzopentanol 8(0.55g, 84% yield, 93% ee).
Pale yellow oil (0.55g, 84% yield)1H NMR(400MHz,CDCl3)δ7.30–7.24(m,2H),7.22– 7.13(m,3H),3.75–3.63(m,2H),2.74–2.51(m,2H),1.70–1.60(m,3H),1.52–1.39(m,2H), 1.31(brs,1H),0.97(d,J＝6.5Hz,3H).13C NMR(100MHz,CDCl3)δ142.94,128.46,128.44, 125.77,61.20,39.91,39.15,33.48,29.34,19.66.ATR-FTIR(cm-1):3344,2929,2869,1604,1496, 1456,746,698.ESI-MS:calculated[C12H18O+H]+:179.1430,found:179.1434.[α]20 D＝14.0(c＝ 0.71,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:93％ee (OJ-H,hexane/i-PrOH＝98/2,detector:254nm,flow rate:1.0mL/min),t1(minor)＝24.9min, t2(major)＝31.4min。
Claims (7)
1. A synthetic method of AMG837 is characterized in that:
racemic propargyl carbonate and a methane tricarboxylate compound are used as initial raw materials, bis- (1, 5-cyclooctadiene) nickel metal is used as a catalyst, a chiral phosphine reagent is used as a ligand, and the target product AMG837 is synthesized by respectively carrying out asymmetric propargyl reaction, hydrolysis reaction and decarboxylation reaction under the assistance of alkali; the synthetic route is as follows:
in the formula: represents a chiral carbon atom; substituent R1Selected from methyl, ethyl, tert-butyl; substituent R2Selected from methyl, ethyl, benzyl;
the alkali is cesium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium hydride;
the chiral phosphine reagent is (R or S) -1,1' -binaphthyl-2, 2' -bis-diphenylphosphine, (R or S) -5,5' -bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl, (R or S) -2,2' -bis [ di (4-methylphenyl phosphine) ] -1,1' -binaphthyl or (R or S) -5,5' -bis (diphenylphosphoryl) -tetrafluoro-di-1, 3-benzodioxolane.
2. The method of synthesis according to claim 1, characterized by the steps of:
step 1: under the argon atmosphere, mixing a bis- (1, 5-cyclooctadiene) nickel metal catalyst and a chiral phosphine ligand in an organic solvent, pre-stirring for 15 minutes, then under the protection of argon, adding a racemic propargyl carbonate compound A, a methane tricarboxylate compound B and alkali into a mixed system, reacting for 12-96 hours at the temperature of room temperature to 50 ℃, and determining a reaction end point by using a thin-layer chromatography dot plate; diluting the reaction system with ethyl acetate, adding water for extraction, extracting a water phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, decompressing and concentrating, and separating by column chromatography to obtain an asymmetric propargylated product C;
step 2: placing the asymmetric propargylated product C in an organic solvent and stirring under an air environment, adding an aqueous sodium hydroxide solution into a reaction system, and then stirring the mixture at room temperature to 80 ℃ and monitoring by TLC; when no starting raw material exists in the reaction system, removing volatile matters in vacuum, adding acetic acid into the reaction system, and heating to react for 6-12 hours under the reflux condition; after the reaction is finished, acetic acid is concentrated in vacuum, the reaction system is diluted by ethyl acetate and extracted by adding water, then the water phase is extracted by ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate and concentrated under reduced pressure, and then the AMG837 or the enantiomer thereof is obtained by column chromatography separation.
3. The method of synthesis according to claim 2, characterized in that:
in the step 1, the molar ratio of the bis- (1, 5-cyclooctadiene) nickel metal catalyst, the chiral phosphine ligand and the methane tricarboxylate compound B is 0.1:0.12: 1; the molar equivalent ratio of the methane tricarboxylate compound B to the racemic propargyl carbonate compound A is 1: 1-3; the molar ratio of the methane tricarboxylate compound B to the alkali is 1: 1-3.
4. A method for synthesizing chiral gamma-methyl benzene amyl alcohol is characterized in that:
using racemic propargyl carbonate and a methane tricarboxylate compound as initial raw materials, using bis- (1, 5-cyclooctadiene) nickel metal as a catalyst, a chiral phosphine reagent as a ligand and Lewis acid as an additive, and respectively performing asymmetric propargyl reaction, hydrolysis reaction, decarboxylation reaction, hydrogenation reaction and reduction reaction under the assistance of alkali to synthesize a target product chiral gamma-methyl benzene pentanol compound; the reaction scheme is as follows:
in the formula: represents a chiral carbon atom; substituent R3Selected from methyl, ethyl, tert-butyl; substituent R4Selected from methyl, ethyl, benzyl;
the alkali is cesium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium hydride;
the chiral phosphine reagent is (R or S) -1,1' -binaphthyl-2, 2' -bis-diphenylphosphine, (R or S) -5,5' -bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl, (R or S) -2,2' -bis [ di (4-methylphenyl phosphine) ] -1,1' -binaphthyl or (R or S) -5,5' -bis (diphenylphosphoryl) -tetrafluoro-di-1, 3-benzodioxolane;
the Lewis acid is copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate or scandium trifluoromethanesulfonate.
5. The method of synthesis according to claim 4, characterized by the steps of:
step 1: under the argon atmosphere, mixing a bis- (1, 5-cyclooctadiene) nickel metal catalyst and a chiral phosphine ligand in an organic solvent, pre-stirring for 15 minutes, then under the protection of argon, adding a racemic propargyl carbonate compound E, a methane tricarboxylate compound F, an alkali and a Lewis acid into a mixed system, reacting for 12-96 hours at the temperature of room temperature to 50 ℃, and determining a reaction end point by using a thin-layer chromatography dot plate; diluting the reaction system with ethyl acetate, adding water for extraction, extracting a water phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, decompressing and concentrating, and separating by column chromatography to obtain an asymmetric propargylated product G;
step 2: placing the asymmetric propargylated product G in an organic solvent and stirring under an air environment, adding an aqueous sodium hydroxide solution into a reaction system, and then stirring the mixture at room temperature to 80 ℃ and monitoring by TLC; when no starting raw material exists in the reaction system, removing volatile matters in vacuum, adding acetic acid into the reaction system, and heating to react for 6-12 hours under the reflux condition; after the reaction is finished, concentrating acetic acid in vacuum, diluting the reaction system with ethyl acetate, adding water for extraction, extracting a water phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain a compound H;
and step 3: dissolving a compound H in an organic solvent in an air environment, slowly adding palladium/carbon at room temperature, and reacting at room temperature to 70 ℃ for 6-12 hours in a hydrogen atmosphere with one atmosphere of pressure; after the reaction is finished, adding ethyl acetate into the reaction system for dilution, filtering through diatomite, concentrating the filtrate under reduced pressure until the filtrate is dry, and using the residue in the next step without purification; and then slowly adding the crude product obtained in the previous step into a mixture of lithium aluminum hydride and an organic solvent at 0 ℃, heating the mixture to room temperature, stirring for 6-12 hours, quenching the reaction with sodium sulfate decahydrate at 0 ℃, filtering through diatomite, concentrating the filtrate under reduced pressure to dryness, and then separating through column chromatography to obtain chiral gamma-methyl benzene pentanol I.
6. The method of synthesis according to claim 5, characterized in that:
in the step 1, the molar ratio of the bis- (1, 5-cyclooctadiene) nickel metal catalyst, the chiral phosphine ligand and the methane tricarboxylate compound F is 0.1:0.12: 1; the molar equivalent ratio of the methane tricarboxylate compound F to the racemic propargyl carbonate compound E is 1: 1-3; the molar ratio of the methane tricarboxylate compound F to the alkali is 1: 1-3; the amount of the Lewis acid added was 0.2 equivalent to that of the methyl trimethyl ester compound F.
7. The method of synthesis according to claim 5, characterized in that:
in the step 3, the addition amount of palladium/carbon is 0.1-0.5 time equivalent of the compound H; the amount of lithium aluminum hydride added is 1.0 to 2.0 times the equivalent of the compound H.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011244915.9A CN112250567B (en) | 2020-11-10 | 2020-11-10 | Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011244915.9A CN112250567B (en) | 2020-11-10 | 2020-11-10 | Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112250567A CN112250567A (en) | 2021-01-22 |
| CN112250567B true CN112250567B (en) | 2021-10-01 |
Family
ID=74265156
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011244915.9A Active CN112250567B (en) | 2020-11-10 | 2020-11-10 | Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112250567B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114573412B (en) * | 2022-02-23 | 2023-12-26 | 杭州凯名庞德生物科技有限公司 | Preparation method of benzoperylene |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3593317B2 (en) * | 2001-03-05 | 2004-11-24 | 独立行政法人 科学技術振興機構 | Microencapsulated metal catalyst |
| DE102005040752A1 (en) * | 2005-08-26 | 2007-03-22 | Universität Dortmund | Iron-catalyzed allylic alkylation |
| CN104876800A (en) * | 2015-04-03 | 2015-09-02 | 江苏绿源精细化工有限公司 | Process for preparing benorilate amyl alcohol |
| WO2020144307A1 (en) * | 2019-01-11 | 2020-07-16 | Basf Se | Preparation of 5-aryl-pentanols |
| CN110590767B (en) * | 2019-08-29 | 2021-10-08 | 南方科技大学 | Method for synthesizing AMG837 |
-
2020
- 2020-11-10 CN CN202011244915.9A patent/CN112250567B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN112250567A (en) | 2021-01-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Luo et al. | Chemoenzymatic Synthesis and Application of Bicyclo [2.2. 2] octadiene Ligands: Increased Efficiency in Rhodium-Catalyzed Asymmetric Conjugate Additions by Electronic Tuning We acknowledge Dr. John Whittall for initial inspiration, Dr. Neil Berry for preliminary modeling and the EPSRC for a Dorothy Hodgkin Postgraduate Award to YL | |
| CN102617547B (en) | A kind of method preparing racemic nicotine | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| Rachwalski et al. | Aziridine ring-containing chiral ligands as highly efficient catalysts in asymmetric synthesis | |
| CN112250567B (en) | Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol | |
| JP4015450B2 (en) | Method for producing optically active alcohol | |
| US5399722A (en) | Process for preparing tert-butyl (3R,5S)-6-hydroxy-3,5--O--isopropylidene-3,5-dihydroxyhexanoate | |
| CN110590767B (en) | Method for synthesizing AMG837 | |
| Bey et al. | Stereospecific alkylation of the Schiff base ester of alanine with 2-substituted-(E)-and-(Z)-vinyl bromides. An efficient synthesis of 2-methyl-(E)-3, 4-didehydroglutamic acid, a potent substrate-induced irreversible inhibitor of L-glutamate-1-decarboxylase | |
| CN103980120A (en) | Synthesis method of D,L-danshensu isopropyl ester | |
| CN110937985A (en) | Synthetic method of paradol | |
| EP3728167B1 (en) | A process for the preparation of crisaborole | |
| CN112321514B (en) | Chiral barbituric acid compound and preparation method thereof | |
| CN112479967B (en) | Biliverdin compound, and preparation method and application thereof | |
| US5434289A (en) | Process for producing optically active β-hydroxyketone | |
| McNulty et al. | An improved synthesis of α-phosphonoenamines based on a modified Peterson olefination | |
| CN109251227B (en) | Chiral compound containing ferrocene skeleton and rigid spiro structure, synthesis and application | |
| CN102627571B (en) | Preparation and synthesis method for chiral ammonium salt | |
| FR2663032A1 (en) | PROCESS FOR THE PREPARATION OF 2-PHENYL-6- (PYRIMIDIN-2-YL) PYRIDINE DERIVATIVES | |
| KR101132870B1 (en) | Concise synthesis of Licochalcone A through water-accelerated [3,3]-sigmatropic rearrangement reaction | |
| JP4812434B2 (en) | Process for producing optically active (S) -2-methyl-6-oxoheptanoic acid | |
| CN106496005B (en) | A kind of synthetic method of 4- (4- chlorphenyl) cyclohexanone | |
| CN114805029A (en) | Related substances of key intermediate of 25-hydroxy dihydro tachysterol and preparation method thereof | |
| JP5233675B2 (en) | Process for producing optically active 2- (2'-piperidinyl) acetate | |
| KR100699928B1 (en) | Process for preparing the intermediate compounds for ppar ? ligands |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |